EP1881967A1 - Composes benzo(d)isoaxol-3-yl-amine substitues utilises comme analgesiques - Google Patents

Composes benzo(d)isoaxol-3-yl-amine substitues utilises comme analgesiques

Info

Publication number
EP1881967A1
EP1881967A1 EP06753695A EP06753695A EP1881967A1 EP 1881967 A1 EP1881967 A1 EP 1881967A1 EP 06753695 A EP06753695 A EP 06753695A EP 06753695 A EP06753695 A EP 06753695A EP 1881967 A1 EP1881967 A1 EP 1881967A1
Authority
EP
European Patent Office
Prior art keywords
benzo
isoxazol
phenyl
thiourea
benzyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP06753695A
Other languages
German (de)
English (en)
Other versions
EP1881967B1 (fr
Inventor
Beatrix Merla
Robert Frank
Gregor Bahrenberg
Wolfgang Schröder
Saskia Zemolka
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gruenenthal GmbH
Original Assignee
Gruenenthal GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gruenenthal GmbH filed Critical Gruenenthal GmbH
Priority to PL06753695T priority Critical patent/PL1881967T3/pl
Priority to SI200630725T priority patent/SI1881967T1/sl
Publication of EP1881967A1 publication Critical patent/EP1881967A1/fr
Application granted granted Critical
Publication of EP1881967B1 publication Critical patent/EP1881967B1/fr
Priority to CY20101100664T priority patent/CY1110209T1/el
Not-in-force legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems

Definitions

  • the present invention relates to substituted benzo [d] isoxazol-3-yl-amine compounds, processes for their preparation, medicaments containing these compounds and the use of these compounds for the preparation of medicaments.
  • K + channels of the molecular subtype KCNQ2 / 3 (Kv7.2 / 7.3) are expressed in neurons of different regions of the central (hippocampus, amygdala) and peripheral (dorsal root ganglia) nervous system and regulate their excitability. Activation of KCNQ2 / 3 K + channels leads to hyperpolarization of the cell membrane and concomitant decrease in the electrical excitability of these neurons.
  • KCNQ2 / 3-expressing neurons of the dorsal root ganglia are involved in the transmission of nociceptive excitations from the periphery to the spinal cord (Passmore et al., 2003). Accordingly, the KCNQ2 / 3 agonist retigabine has demonstrated analgesic efficacy in preclinical neuropathy and inflammatory pain models (Blackburn-Munro and Jensen, 2003; Passmore et al., 2003; Dost et al., 2004).
  • the KCNQ2 / 3 K + channel thus provides a suitable starting point for the treatment of pain; especially from pain selected from the group consisting of chronic pain, neuropathic pain, inflammatory pain and muscular pain (Nielsen et al., 2004), in particular neuropathic and inflammatory pain.
  • the KCNQ2 / 3 K + channel is a suitable target for the therapy of a variety of other diseases such as migraine (US2002 / 0128277), cognitive disorders (Gribkoff, 2003), anxiety (Korsgaard et al., 2005), epilepsy (Wickenden et al., 2004), and urinary incontinence (Streng et al., 2004).
  • substituted benzo [d] isoxazol-3-yl-amine compounds of the general formula I given below are suitable for the treatment of pain and also have an excellent affinity for the KCNQ2 / 3K + channel and are therefore suitable for treatment of disorders or diseases mediated, at least in part, by KCNQ2 / 3K + channels.
  • R 1 , R 2 , R 3 and R 4 independently of one another, are each for
  • heteroatom ring member having cycloaliphatic radical which condenses with a mono- or polycyclic ring system and / or bonded via a linear or branched alkylene, alkenylene or alkynylene group can be;
  • aryl or heteroaryl radical which may be condensed with a monocyclic or polycyclic ring system and / or bonded via a linear or branched alkylene, alkenylene or alkynylene group,
  • R 7 and R 8 independently of one another, each for
  • R 15 or represent a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic radical, or
  • R 7 and R 8 together with the nitrogen atom connecting them form a saturated or unsaturated, unsubstituted or at least monosubstituted, optionally at least one further heteroatom ring member having heterocycloaliphatic radical,
  • R 9 , R 10 , R 11 and R 16 are each independently, for
  • ring member having cycloaliphatic radical which may be condensed with a mono- or polycyclic ring system and / or bound via a linear or branched alkylene group;
  • R 12 and R 13 independently of each other, each for H or a linear or branched, saturated or unsaturated, unsubstituted or at least monosubstituted aliphatic radical, or
  • R 12 and R 13 together with the nitrogen atom connecting them form a saturated or unsaturated, unsubstituted or at least monosubstituted, optionally at least one further heteroatom ring member having heterocycloaliphatic radical,
  • a cycloaliphatic radical having a mono- or polycyclic ring system and / or being bonded via a linear or branched alkylene group
  • R 21 and R 22 are each independently H
  • a cycloaliphatic radical having a mono- or polycyclic ring system and / or being bonded via a linear or branched alkylene group
  • (hetero) cycloaliphatic radicals which may be mentioned are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, azepanyl, diazepanyl and dithiolanyl ,
  • a monocyclic or polycyclic ring system is understood to mean monocyclic or polycyclic hydrocarbon radicals which may be saturated or unsaturated and may optionally have 1, 2, 3, 4 or 5 heteroatom (s) as ring member (s) which are independently selected from the group consisting of oxygen, nitrogen and sulfur.
  • a mono- or polycyclic ring system may, for example, be condensed (fused) with an aryl radical or a heteroaryl radical.
  • a polycyclic ring system such as a bicyclic ring system
  • the different rings each independently of one another, can have a different degree of saturation, ie be saturated or unsaturated. Preference is given to a bicyclic ring system.
  • aryl radicals which are condensed with a monocyclic or polycyclic ring system are (1,3) -benzodioxolyl and (1,4) -benzodioxanyl.
  • the rings of the abovementioned mono- or polycyclic ring systems are each 5-, 6- or 7-membered and may in each case optionally have 1, 2, 3, 4 or 5 heteroatom (s) as ring member (s) which are independent of each other selected from the group consisting of oxygen, nitrogen and sulfur.
  • alkyl, -OC ⁇ -Alky !, - NH 2, -NO 2, -0-CF 3, -S-CF 3, -SH, -Sd.g alkyl, -C 1-5 alkyl, - C (O) -OH, -C ( O) -O-Ci -5 - alkyl, -NH-C 1-5 alkyl, -N (C 1-5 alkyl) 2, -O-phenyl, - O-benzyl, phenyl and benzyl be substituted, wherein in each case the cyclic part of the radicals -O-phenyl, -O-benzyl, phenyl and benzyl with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of F , Cl, Br, -OH, -CF 3, -SF 5, -CN, -NO 2, - Ci -5 alkyl, -O-Ci-s-alkyl, -0-CF 3,
  • aryl radicals which may be mentioned are phenyl and naphthyl (comprising 1-naphthyl and 2-naphthyl).
  • heteroaryl radicals which may be mentioned are thiophenyl, furanyl, pyrrolyl, pyrazolyl, pyrazinyl, pyranyl, triazolyl, pyridinyl, imidazolyl, indolyl, isoindolyl, benzo [b] furanyl, benzo [b] thiophenyl, thiazolyl, oxazolyl, isoxazolyl, pyridazinyl, pyrazinyl, Pyrimidinyl, indazolyl, quinoxalinyl, quinolinyl and isoquinolinyl.
  • the abovementioned aliphatic radicals may preferably have 1-10 or 2-10 carbon atoms in the alkyl moiety and preferably with optionally 1, 2, 3, 4, 5, 6, 7 , 8 or 9 substituents independently of one another selected from the group consisting of F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -SH, -O (C 1-5 -alkyl), S (Ci-5-alkyl), -NH (C 1-5 alkyl), -N (Ci ⁇ alkyl) (C ⁇ alkyl), - OCF 3 , C ß - ⁇ -cycloalkyl and -SCF 3 substituted be.
  • Alkenyl radicals have at least one, preferably 1, 2, 3 or 4 C-C double bonds and alkynyl radicals have at least one, preferably 1, 2, 3 or 4 C-C triple bonds.
  • Alkyl radicals are preferably selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, neo-pentyl and n-hexyl optionally substituted by 1, 2, 3, 4, 5, 6, 7, 8 or 9 substituents independently selected from the group consisting of F, Cl, Br, I, -CN, -NO 2 , -OH, - NH 2 , -SH, -OCH 3 , -O-C 2 H 5 , -SCH 3 , -SC 2 H 5 , -OCF 3 , -SCF 3 , -NH-CH 3 , -N (CHg) 2 , - N (C 2 H 5 J 2 and -N (CH 3 ) (C 2 H 5 ) may be substituted.
  • alkenyl radicals selected from the group consisting of vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-buten-2-yl, 1-pentenyl, 2- Pentenyl, 3-pentenyl and 4-pentenyl optionally with 1, 2 or 3 substituents independently of one another selected from the group consisting of F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -SH, -OCH 3 , -O-C 2 H 5 , -SCH 3 , -SC 2 H 5 , -OCF 3 , - SCF 3 , -NH-CH 3 , -N (CH 3 ) 2 , -N ( C 2 Hs) 2 and -N (CH 3 ) (C 2 H 5 ) may be substituted.
  • alkynyl radicals selected from the group consisting of ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and 3-butynyl, optionally with 1, 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, I, -CN, -NO 2 , -OH, -NH 2 , -SH 1 -OCH 3 , -O-C 2 H 5 , -SCH 3 , -SC 2 H 5 , -OCF 3 , -SCF 3 , -NH-CH 3 , -N (CH 3 ) 2 ( -N (C 2 Hg) 2 and -N (CH 3 ) (C 2 H 5 ).
  • R 1 , R 2 , R 3 and R 4 independently of one another, are each for
  • n 1, 2 or 3, wherein R 6 is H, C 3-8 cycloalkyl or C is -6 alkyl, and R 25 is aryl or heteroaryl
  • R 7 and R 8 independently of one another, each for
  • R 7 and R 8 together with the nitrogen atom connecting them as ring member, form a radical selected from morpholine, piperidine or pyrrolidine;
  • R 12 and R 13 together with the nitrogen atom connecting them as ring member form a radical selected from morpholine, piperidine or pyrrolidine;
  • R 21 and R 22, independently of one another, are each H, d.io alkyl, C 2- io alkenyl, C 2- I 0 alkynyl; C 3-8 cycloalkyl; - (Ci- 5 alkylene) -C 3-8 -
  • cycloalkyl cycloalkyl; heterocycloalkyl; - (Ci ⁇ -AlkylenJ-heterocycloalkyl; aryl; heteroaryl;
  • Ci-io alkyl, C 2- I 0 alkenyl, and C i 0 2- alkynyl radicals are each linear or branched and optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of F; Cl; Br; COOH; COOC 1-4 alkyl; -CN; -OH; SH; -OC 1-2 alkyl; -S-Ci.
  • 2- alkyl and -NH 2 may be substituted,
  • C 3-8 -cycloalkyl radicals in each case optionally having 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of F; Cl; Br; -CN; -OH; SH; -C. 5- alkyl; -OC 1-2 alkyl; -SC 1-2 alkyl and -NH 2 may be substituted,
  • heterocycloalkyl radicals are each 4-, 5-, 6- or 7-membered, 1 or 2 heteroatoms independently of one another selected from the group consisting of oxygen, sulfur and nitrogen as ring member (s) and optionally with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of F; Cl; Br; -CN; -OH; SH; -C 1-5 alkyl; -Od.
  • 2- alkyl; -SC 1-2 alkyl and -NH 2 may be substituted,
  • each of the aforementioned aryl radicals represents a phenyl, anthracenyl or naphthyl radical selected from 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of F; Cl; Br; I; -CF 3 ; -
  • OCF 3 ; -SCF 3 ; C ( O) C 1-5 alkyl; ⁇ O->', ⁇ s / 3; NO 2 ; cyclohexyl;
  • -C ( O) -OC 1-5 alkyl; -NH 2 ; -N (H) (C 1-5 alkyl); -N (Ci -5 alkyl) (C 1-5 alkyl);
  • Thiophenyl (thienyl), furanyl and pyridinyl may be substituted
  • n 1, 2 or 3 wherein R 6 is H or C -6 alkyl, and R 25 is aryl or heteroaryl
  • R 7 and R 8 independently of one another, each for
  • R 7 and R 8 together with the nitrogen atom connecting them as ring member, form a radical selected from morpholine, piperidine or pyrrolidine; R 9 , R 10 independently, each for
  • Ci-io alkyl C 2-10 alkenyl, C 2- I 0 alkynyl; C 3 . 8 -cycloalkyl; - (C 1 2 2 ⁇ d er 3 - alkylene) - C 3-8 -cycloalkyl; heterocycloalkyl; - (C 1i 2 oc e r 3 -alkylene) -heterocycloalkyl; aryl; heteroaryl; - ( - (C 1i 2 ⁇ de r 3 -alkylene) heteroaryl;
  • the aforementioned d.-io-alkyl, C 2- io-alkenyl and C 2-1 o-alkynyl radicals are each linear or branched and optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently of one another from the group consisting of F; Cl; Br; -CN; COOH; COOC 1-4 alkyl; -OH; SH; -OC 1-2 alkyl; -SC 1-2 alkyl and -NH 2 may be substituted,
  • Ci-C4 alkyl, C 2-4 alkenyl and C 2-4 alkynyl radicals are each linear or branched and optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the Group consisting of F; Cl; Br; -CN; -OH; -OCH 3 and -NH 2 may be substituted,
  • Cs- ⁇ -cycloalkyl radicals in each case optionally having 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of F; Cl; Br; -CN; -OH; -CH 3 ; -C 2 H 5 ; -OCH 3 ; and -NH 2 can be substituted,
  • heterocycloalkyl radicals are each 4-, 5-, 6- or 7-membered, 1 or 2 heteroatoms independently selected from the group consisting of oxygen, sulfur and nitrogen as ring member (s) and optionally having 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of F; Cl; Br; -CN; -OH; -CH 3 ; -C 2 H 5 ; -OCH 3 ; and -NH 2 can be substituted,
  • each of the aforementioned aryl radicals represents a phenyl, anthracenyl or naphthyl radical selected from 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of F; Cl; Br; -CF 3 ; -
  • heteroaryl radicals in each case stand for a furanyl, thienyl (thiophenyl) or pyridinyl radical and optionally with 1, 2, 3, 4 or 5 substituents independently of one another selected from the group consisting of F; Cl; Br; -CF 3 ; -OCF 3 ; -SCF 3 ; -SF 5 ; -CN; -OH; Methyl; ethyl; n-propyl; iso-propyl; n-butyl; iso-butyl; sec-butyl; tert-butyl; methoxy; ethoxy; - NH 2 ; -N (CH 3 ) 2 ; -N (C 2 Hs) 2 ; phenyl; Phenoxy, benzyl; Thiophenyl (thienyl), furanyl and pyridinyl may be substituted,
  • n is 1.
  • Ci.io-alkyl branched or unbranched, saturated or unsaturated, unsubstituted or substituted with OCH 3 , COOCH 3 or COOC 2 H 5 ; C 3 to C 6 cycloalkyl, where the cycloalkyl group may be linked via a CH 2 group; C 5-6 - heterocycloalkyl wherein the heterocycloalkyl group may be linked via a CH 2 group; stands.
  • R 21 is H and R 22 is benzyl, phenyl, 2-methylphenyl, phenethyl, 2-isopropylphenyl, 2-chlorophenyl, 4-fluorobenzyl, 1- (4-fluorophenyl) ethyl, 4-chlorobenzyl, 4 -Chlorophenethyl, 4-nitrophenyl, 4-acetylphenyl, 3-carboxyphenyl, 3-methylbenzoate, 4-ethylbenzoate, 2,6-diethylphenyl, 3-chloro-4-methyl-phenyl, 2-methoxyethyl, 3-methoxypropyl , Cyclopentyl, cyclohexyl, 3-pyridyl, 4-dimethylaminophenyl, 4-diethylaminophenyl, CH 2 COOCH 3 , CH (CH 3 ) COOC 2 H 5 , CH (CH 3 ) CH 2 COOC 2 H
  • R 25 is phenyl, anthracenyl, pyridyl, thienyl or furyl, in each case unsubstituted or mono- or polysubstituted by CF 3 , SCF 3 , C 1-4 -alkyl, Cl, NO 2 , O-acetyl, OCH 3 , F, O-phenyl, OCF 3 , Br, O-benzyl, 0-AHyI, phenyl, I, CN or OH, preferably phenyl unsubstituted or substituted with said radicals.
  • R 25 is 4-trifluoromethylphenyl, 4-SCF 3 -phenyl, 2-methylphenyl, phenyl, anthracenyl, 4-CI-phenyl, 4-OCF 3 -phenyl, 4-n-butylphenyl, 3 (3-CF 3 -phenoxy) -phenyl, 4-OCHF 2 -phenyl, 3,5-dimethylphenyl, 3-bromo-4-methoxyphenyl, 4-benzyloxy-3,5-dimethylphenyl, 3-nitrophenyl, 3-methoxy 4- (acetylmethyl) -phenyl, 2,4,5-trimethoxyphenyl, 4-ethylphenyl, 3,4-dichlorophenyl, 2,3,5-trifluorophenyl, 4-phenoxyphenyl, 3-chloro-4-fluorophenyl, 3-benzyloxy phenyl, 3-bromo-4,5-dimethoxyphenyl, 3-flu
  • Another object of the present invention is a process for the preparation of the substituted benzo [d] isoxazol-3-yl-amine compounds according to the invention, according to which an optionally substituted 2-fluoro-benzonitrile compound of the general formula II,
  • radicals R 1 , R 2 , R 3 and R 4 have the abovementioned meaning, in a reaction medium, preferably selected from the group consisting of diethyl ether, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, dimethylformamide and dichloromethane, in the presence of a base, preferably in Presence of at least one alkali metal alcoholate salt, particularly preferably in the presence of an alkali metal alcoholate salt selected from the group consisting of potassium methoxide, sodium methoxide, potassium tert-butoxide and sodium tert-butylate with acethydroxamic acid of the formula III
  • radicals R 1 -R 4 have the abovementioned meaning and the radical R 5 is a hydrogen radical, is reacted, this is optionally purified and / or optionally isolated,
  • R 1 , R 2 , R 3 , R 4 have the abovementioned meaning
  • R 22 is the has the abovementioned meaning
  • R 21 is a hydrogen radical, in a reaction medium, preferably selected from the group consisting of acetonitrile, toluene, dimethylformamide, benzene, ethanol, methanol and corresponding mixtures, in the presence of at least one base, preferably in the presence at least a metal hydride salt or a metal alcoholate salt, more preferably in the presence of a metal hydride salt or a metal alcoholate salt selected from the group consisting of sodium hydride, potassium hydride, potassium tert-butoxide, sodium tert-butoxide, potassium methoxide, sodium methoxide, sodium ethoxide and potassium ethoxide, with at least one compound of general formula LG-R 21 ,
  • At least one compound of the general formula I in which R 1 , R 2 , R 3 , R 4 have the abovementioned meaning and R 5 is H, in a reaction medium, preferably selected from the group consisting of acetonitrile, toluene, dimethylformamide , Benzene, ethanol, methanol, DCM, trifluoroacetic acid and corresponding mixtures, in the presence of at least one base, preferably in the presence of at least one metal hydride salt or a metal alcoholate salt or triethylsilane, more preferably in the presence of triethylsilane, a metal hydride salt or a metal alcoholate salt selected from the group consisting of Sodium hydride, potassium hydride, potassium tert-butoxide, sodium tert-butoxide, potassium methoxide, sodium methoxide, sodium ethoxide and potassium, with at least one compound of the general formula R 30 C ( O) H or R 6 C (O
  • radical R 30 is defined in a particular compound, this means that in this case in structures of the general formula IR 5 is CH 2 R 30 .
  • the intermediate and end products obtained according to the above-described reactions can each be purified and / or isolated, if desired and / or required, by customary methods known to those skilled in the art.
  • Suitable purification methods are, for example, extraction methods and chromatographic methods, such as column chromatography or preparative chromatography, and HPLC.
  • the free bases of the respective substituted benzo [d] isoxazol-3-yl-amine compounds according to the invention can be obtained, for example, by reaction with an inorganic or organic acid, preferably with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid , Acetic, oxalic, maleic, malic, succinic, tartaric, mandelic, fumaric, lactic, citric, glutamic or aspartic acid, into the corresponding salts, preferably physiologically acceptable salts.
  • an inorganic or organic acid preferably with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid , Acetic, oxalic, maleic, malic, succinic, tartaric, mandelic,
  • the free bases of the respective substituted benzo [d] isoxazol-3-yl-amine compounds of the present invention may also be reacted with the free acid or a salt of a sugar substitute, such as e.g. Saccharin, cyclamate or acesulfame, be converted into the corresponding physiologically acceptable salts.
  • a sugar substitute such as e.g. Saccharin, cyclamate or acesulfame
  • the free acids of the substituted benzo [d] isoxazol-3-yl-amine compounds according to the invention can be converted into the corresponding physiologically tolerable salts by reaction with a suitable base.
  • the substituted benzo [d] isoxazol-3-yl-amine compounds according to the invention may optionally, as well as the corresponding acids, the corresponding bases or salts of these compounds, according to conventional methods known to those skilled in the form of their solvates, preferably in the form their hydrates. If the substituted benzo [d] isoxazol-3-yl-amine compounds according to the invention are obtained in the form of a mixture of their stereoisomers, preferably in the form of their racemates or other mixtures of their different enantiomers and / or diastereomers, these the method known to those skilled in the art are separated and optionally isolated.
  • chromatographic separation processes in particular liquid chromatography processes under atmospheric pressure or under elevated pressure, preferably MPLC and HPLC processes, and also fractional crystallization processes.
  • individual enantiomers for example by means of HPLC on chiral stationary phase or by crystallization with chiral acids, such as (+) - tartaric acid, (-) - tartaric acid or (+) - 10-camphorsulfonic acid, formed diastereomeric salts are separated.
  • substituted benzo [d] isoxazol-3-yl-amine compounds according to the invention and in each case the corresponding acids, bases, salts and solvates are suitable as pharmaceutical active ingredients in medicaments.
  • Another object of the present invention is therefore a medicament containing at least one substituted benzo [d] isoxazol-3-yl-amine compound according to the invention and optionally one or more pharmaceutically acceptable excipients.
  • medicaments according to the invention are suitable for influencing KCNQ2 / 3 channels and in particular exert an agonistic action.
  • the medicaments according to the invention are preferably suitable for the treatment of disorders or diseases which are mediated at least in part by KCNQ2 / 3 channels.
  • the medicament of the invention is preferably suitable for the treatment of one or more diseases selected from the group consisting of pain, preferably pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, muscular pain and inflammatory pain, migraine; Epilepsy, anxiety and Urinary incontinence.
  • the medicaments according to the invention are particularly preferably suitable for the treatment of pain, very particularly preferably of chronic pain, neuropathic pain, inflammatory pain and muscular pain.
  • Another object of the present invention is the use of at least one substituted benzo [d] isoxazol-3-yl-amine compound and optionally one or more pharmaceutically acceptable excipients for the manufacture of a medicament for the treatment of disorders or diseases that at least partially by KCNQ2 / 3 channels are taught.
  • Preferred is the use of at least one substituted benzo [d] isoxazol-3-yl-amine compound and optionally one or more pharmaceutically acceptable excipients for the manufacture of a medicament for the treatment of pain, preferably of pain selected from the group consisting of acute pain , chronic pain, neuropathic pain, muscular pain and inflammatory pain; Migraine; Epilepsy, anxiety and urinary incontinence.
  • At least one substituted benzo [d] isoxazol-3-yl-amine compound according to the invention and optionally one or more pharmaceutically acceptable excipients for the preparation of a medicament for the treatment of pain, most preferably of chronic pain, neuropathic pain, inflammatory pain and muscular pain.
  • the medicament according to the invention can be used as a liquid, semisolid or solid dosage form, for example in the form of injection solutions, drops, juices, syrups, sprays, suspensions, tablets, patches, capsules, patches, suppositories, ointments, creams, lotions, gels, emulsions, aerosols or in multiparticulate form, for example in the form of pellets or granules, optionally compressed into tablets, filled into capsules or suspended in a liquid, are present and as such also administered.
  • the pharmaceutical composition according to the invention usually contains further physiologically tolerated pharmaceutical excipients which may be preferably selected from the group consisting of support materials, fillers, solvents, diluents, surfactants, dyes, preservatives, disintegrants, lubricants, lubricants, flavors and binders.
  • physiologically acceptable excipients depend on whether the drug is oral, subcutaneous, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal, rectal or topical, for example, skin infections, mucous membranes and on the eyes, to be applied.
  • Preparations in the form of tablets, dragees, capsules, granules, pellets, drops, juices and syrups are preferred for oral administration, solutions, suspensions, readily reconstitutable dry preparations and sprays for parenteral, topical and inhalative administration.
  • the substituted benzo [d] isoxazol-3-yl-amine compounds used in the medicament according to the invention can be present in a depot, in dissolved form or in a plaster, optionally with the addition of skin penetration-promoting agents, as suitable percutaneous administration preparations. Orally or percutaneously applicable preparation forms, the respective substituted benzo [d] isoxazol-3-yl-amine compound according to the invention can also release delayed.
  • compositions of the present invention are prepared by conventional means, devices, methods and methods known in the art, as described, for example, in "Remington's Pharmaceutical Sciences", by AR Gennaro, 17th Ed., Mack Publishing Company, Easton, Pa , 1985, especially in part 8, chapters 76 to 93. The corresponding description is hereby incorporated by reference and is considered part of the disclosure.
  • the amount of the respective substituted benzo [d] isoxazol-3-yl-amine compound of the invention to be administered to the patient may vary and depends, for example, on the weight or age of the patient as well as on the mode of administration, the indication and the severity of the disease. Usually 0.005 to 100 mg / kg, preferably 0.05 to 75 mg / kg of body weight of the patient of at least one such compound of the invention is administered.
  • the backbone of the benzisoxazoles according to the invention was prepared analogously to the instructions of Palermo (M.G. Palermo, Tetrahedron Lett., 1996, 37, 17, 2885-2886). The corresponding description is hereby incorporated by reference and thus forms part of the present disclosure. Notwithstanding the above provision, the purification of the benzisoxazole compounds takes place in part by precipitating the corresponding HCl salt.
  • Acethydroxamic acid (1.1 equivalents) in DMF (1.45 ml / mmol acethydroxamic acid) was suspended in a three-necked flask. Under inert gas, potassium f-butylate (1.1 equiv.) was added. The mixture was 30 min. stirred at room temperature and then treated with the optionally substituted 2-fluoro-benzonitrile (1 equiv.). The reaction mixture was heated to 50 0 C and stirred for 1 h at this temperature. After cooling, the reaction mixture was added to a mixture (1, 8 ml / mmol Acethydroxamklare) from equal volumes of saturated NaCl solution and ethyl acetate and stirred well for 30 min.
  • the phases were separated and the aqueous phase was extracted 3 times with ethyl acetate (in each case 0.8 ml / mmol of acethydroxamic acid).
  • the organic phases were combined and washed 3 times with saturated NaCl solution (in each case 0.8 ml / mmol of acethydroxamic acid) and then dried over magnesium sulfate.
  • the magnesium sulfate was filtered off and the filtrate was concentrated first on a rotary evaporator and then on the oil pump.
  • aryl or heteroaryl radical which may be condensed with a mono- or polycyclic ring system and attached via a linear or branched alkylene group.
  • solution I 100 .mu.mol of benzisoxazole solution
  • solution II 100 .mu.mol of the corresponding aldehyde
  • solution III 0.1 M triethylsilane in DCM, 0.25 M trifluoroacetic acid in DCM, 1, 2 ml
  • the threaded glass was sealed with a septum cap, and the reaction solution 16h under reflux at 60 ° C in stirred. Subsequently, the reaction solution was brought to RT and treated with 1, 5 ml of 7% NaCO 3 solution adjusted alkaline and 30 min. mixed. The stir bar was filtered off and the vessel rinsed with 1.5 ml DCM.
  • the organic phase was taken off and collected.
  • the aqueous phase was mixed with 2 ml DCM, vortexed and 15 min. intensely mixed. After centrifugation, the organic phases were separated and the first fraction united. The aqueous phase was extracted analogously a second time with DCM. Subsequently, the combined organic phases were dried over a MgS ⁇ 4 cartridge and concentrated in the GeneVac. The purification was carried out by means of HPLC.
  • the suspension was briefly swelled and poured directly over a 0.45 .mu.m GHP filter Funnel.
  • the test tube was rinsed with 7.5 ml DCM and then the suspension was filtered off in the filter funnel with the aid of compressed air.
  • the clear organic phase was concentrated in Gene-Vac. The purification was carried out by HPLC.
  • KCNQ2 / 3-expressing CHO-K1 cells or CHO-K1 strain strain cells were seeded on coated poly-D-lysine plates black / clear (Falcon / BD, order number: 356640). in a concentration of 20000 cells / 1 OO ⁇ l MEM alpha, 50 ml FCS, 5.5 ml P / S / G Solution (100x) and subsequent incubation for 20 - 24 h in the incubator (37 ° C, 5% CO 2 ).
  • the HBSS / Hepes working solution and the FMP / HBSS / Hepes mixture are prepared according to the following scheme:
  • test substances Stock solution 2 mM in 100% DMSO
  • Drugplates Costar 96 well plates, Cat No. 3795
  • dilution of the test substances is carried out by addition of HBSS / Hepes buffer to a concentration of 30 ⁇ M (concentrated 3 ⁇ ).
  • the cell-covered assay plates are washed once with 200 ⁇ l of HBSS / Hepes (Cellwash Washer, Labsystems, cat # 5161550) and residual volumes are removed by tapping the inverted plate twice. Subsequently, the cell plates are each mixed with 100 ⁇ l of the FMP / HBSS / Hepes working solution and incubated for 1 h in a CO 2 incubator at 37 ° C. and 5% CO 2 .
  • the measurement is performed on the FLIPR III instrument from Molecular Devices (96 format, using the 540-590 nm bandpass filter in the # 2 localization).
  • the experimental setup of the FLIPR software is to select Filter # 2.
  • the cell plates are placed alternately with the substance plates in the input stacker. From the cell plates, a signal test is carried out in each case before substance addition.
  • the addition of the test substances (addition volume 50 ⁇ l, 3 ⁇ concentrated, final concentration 10 ⁇ M) into the cell plate cavities to a total volume of 150 ⁇ l / well is then carried out by the pipetting unit of the FLIPR.
  • the key data of the FLIPR program are:
  • EC50 / IC50 values are calculated using the Graph Päd Prism software.
  • the retigabine (10 ⁇ M) induced current increase at -40 mV was first registered as a positive control. After complete washing out of the retigabine effect (duration: 80 s), the test substance (10 ⁇ M) was applied. The increase in current induced by the test substance was normalized to the retigabine effect and reported as relative efficacy (see below).

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Addiction (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Pulmonology (AREA)
  • Urology & Nephrology (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Cardiology (AREA)
  • Dermatology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Psychology (AREA)
  • Rheumatology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Hospice & Palliative Care (AREA)
  • Anesthesiology (AREA)
  • Vascular Medicine (AREA)
  • Child & Adolescent Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Compositions Of Macromolecular Compounds (AREA)
EP06753695A 2005-05-18 2006-05-18 Composes benzo(d)isoaxol-3-yl-amine substitues utilises comme analgesiques Not-in-force EP1881967B1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
PL06753695T PL1881967T3 (pl) 2005-05-18 2006-05-18 Podstawione benzo[d]izoksazol-3-iloaminy jako środki przeciwbólowe
SI200630725T SI1881967T1 (sl) 2005-05-18 2006-05-18 Substituirane benzo(d)izoksazol-3-il-aminske spojine kot analgetiki
CY20101100664T CY1110209T1 (el) 2005-05-18 2010-07-15 Υποκατεστημενες ενωσεις βενζο(d)ισοξαζολ-3-υλ-αμινης σαν αναλγητικα

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE102005023589 2005-05-18
DE102005038947A DE102005038947A1 (de) 2005-05-18 2005-08-16 Substituierte Benzo[d]isoxazol-3-yl-amin-Verbindungen und deren Verwendung in Arzneimitteln
PCT/EP2006/004700 WO2006122800A1 (fr) 2005-05-18 2006-05-18 Composes benzo(d)isoaxol-3-yl-amine substitues utilises comme analgesiques

Publications (2)

Publication Number Publication Date
EP1881967A1 true EP1881967A1 (fr) 2008-01-30
EP1881967B1 EP1881967B1 (fr) 2010-04-28

Family

ID=36699120

Family Applications (2)

Application Number Title Priority Date Filing Date
EP06753695A Not-in-force EP1881967B1 (fr) 2005-05-18 2006-05-18 Composes benzo(d)isoaxol-3-yl-amine substitues utilises comme analgesiques
EP06742972A Not-in-force EP1888541B1 (fr) 2005-05-18 2006-05-18 Composes benzo(d)isoxazol-3-yl-amine et leurs utilisations comme ligands recepteurs vanilloides

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP06742972A Not-in-force EP1888541B1 (fr) 2005-05-18 2006-05-18 Composes benzo(d)isoxazol-3-yl-amine et leurs utilisations comme ligands recepteurs vanilloides

Country Status (16)

Country Link
US (2) US7977360B2 (fr)
EP (2) EP1881967B1 (fr)
JP (2) JP2008540597A (fr)
AT (2) ATE466002T1 (fr)
AU (1) AU2006249065B2 (fr)
CA (2) CA2608386A1 (fr)
CY (2) CY1109568T1 (fr)
DE (3) DE102005038947A1 (fr)
DK (2) DK1881967T3 (fr)
ES (2) ES2331259T3 (fr)
HK (1) HK1112238A1 (fr)
PL (2) PL1888541T3 (fr)
PT (2) PT1881967E (fr)
RU (1) RU2416607C2 (fr)
SI (2) SI1888541T1 (fr)
WO (2) WO2006122800A1 (fr)

Families Citing this family (46)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102005038947A1 (de) * 2005-05-18 2006-11-30 Grünenthal GmbH Substituierte Benzo[d]isoxazol-3-yl-amin-Verbindungen und deren Verwendung in Arzneimitteln
US20100080773A1 (en) 2008-09-26 2010-04-01 Sdg, Inc. Orally Bioavailable Lipid-Based Constructs
US8557872B2 (en) 2008-01-28 2013-10-15 Amorepacific Corporation Compounds, isomer thereof, or pharmaceutically acceptable salts thereof as vanilloid receptor antagonist; and pharmaceutical compositions containing the same
CN102137851B (zh) 2008-07-02 2014-08-27 株式会社爱茉莉太平洋 作为香草素受体拮抗剂的化合物、其异构体或其药学可接受的盐以及包含它们的药物组合物
US8349852B2 (en) 2009-01-13 2013-01-08 Novartis Ag Quinazolinone derivatives useful as vanilloid antagonists
TWI504395B (zh) 2009-03-10 2015-10-21 Substituted 3-amino-2-mercaptoquinoline as a KCNQ2 / 3 modifier
AU2010223555A1 (en) * 2009-03-10 2011-11-03 Grünenthal GmbH Substituted 3-aminoisoxazolopyridines as KCNQ2/3 modulators
TW201038565A (en) 2009-03-12 2010-11-01 Gruenenthal Gmbh Substituted 2-mercapto-3-aminopyridines as KCNQ2/3 modulators
TWI461197B (zh) 2009-03-12 2014-11-21 2-mercaptoquinoline-3-carboxamide as a KCNQ2 / 3 modifier
EP2531510B1 (fr) 2010-02-01 2014-07-23 Novartis AG Dérivés de pyrazolo[5,1-b]utilisés en tant qu'antagonistes du récepteur de crf-1
WO2011092293A2 (fr) 2010-02-01 2011-08-04 Novartis Ag Dérivés de cyclohexylamide utilisés en tant qu'antagonistes du récepteur du crf
US8835444B2 (en) 2010-02-02 2014-09-16 Novartis Ag Cyclohexyl amide derivatives as CRF receptor antagonists
KR20120120416A (ko) 2010-02-11 2012-11-01 벤더르빌트 유니버시티 Ｍｇｌｕｒ4 알로스테릭 강화제로서 벤즈이속사졸 및 아자벤즈이속사졸, 조성물, 및 신경 기능이상을 치료하는 방법
NZ604745A (en) 2010-08-27 2015-01-30 Gruenenthal Chemie Substituted 2-oxy-quinoline-3-carboxamides as kcnq2/3 modulators
EP2609086B1 (fr) 2010-08-27 2015-02-25 Grünenthal GmbH 2-oxo- et 2-thioxo-dihydroquinoléine-3-carboxamides substitués comme modulateurs de kcnq2/3
US8470852B2 (en) 2010-08-27 2013-06-25 Gruenenthal Gmbh Substituted 2-amino-quinoline-3-carboxamides as KCNQ2/3 modulators
MX2013002295A (es) 2010-09-01 2013-05-09 Gruenenthal Gmbh 1-oxo-dihidroisoquinolin-3-carboxamidas sustituidas como moduladores de kcnq2/3.
EP2773641B1 (fr) 2011-10-31 2017-09-27 Xenon Pharmaceuticals Inc. Biaryléthersulfonamides et leur utilisation en tant qu'agents thérapeutiques
CA2853439A1 (fr) 2011-10-31 2013-05-10 Xenon Pharmaceuticals Inc. Composes de benzenesulfonamide et leur utilisation en tant qu'agents therapeutiques
MX2014014234A (es) 2012-05-22 2015-05-07 Genentech Inc Benzamidas n-sustituidas y su uso en el tratamiento del dolor.
KR101663436B1 (ko) 2012-07-06 2016-10-06 제넨테크, 인크. N-치환된 벤즈아미드 및 이의 사용 방법
KR20150131233A (ko) 2013-03-14 2015-11-24 제넨테크, 인크. 치환된 트리아졸로피리딘 및 이의 사용 방법
US9493429B2 (en) 2013-03-15 2016-11-15 Genentech, Inc. Substituted benzoxazoles and methods of use thereof
CR20160296A (es) 2013-11-27 2016-09-20 Genentech Inc Benzamidas sustituidas y métodos para usarlas
EP3092234B1 (fr) 2013-12-20 2018-02-14 Gilead Sciences, Inc. Composés hétérocycliques annelées comme modulateurs des canaux ioniques.
US10005724B2 (en) 2014-07-07 2018-06-26 Genentech, Inc. Therapeutic compounds and methods of use thereof
WO2016024233A1 (fr) 2014-08-13 2016-02-18 Auckland Uniservices Limited Inhibiteurs de tryptophane dioxygénases (ido1 et tdo) et leur utilisation en thérapie
JP6612874B2 (ja) 2014-12-16 2019-11-27 アクソファント サイエンシーズ ゲーエムベーハー α７−ニコチン性アセチルコリン受容体のアゴニストとしてのジェミナル置換キヌクリジンアミド化合物
WO2016096709A1 (fr) * 2014-12-16 2016-06-23 Eudendron S.R.L. Dérivés hétérocycliques modulant l'activité de certaines protéines kinases
KR20180008761A (ko) 2015-05-22 2018-01-24 제넨테크, 인크. 치환된 벤즈아미드 및 이의 이용 방법
RU2017145964A (ru) 2015-06-10 2019-07-10 Аксовант Сайенсиз Гмбх Аминобензизоксазольные соединения в качестве агонистов α7-никотиновых ацетилхолиновых рецепторов
US10428062B2 (en) 2015-08-12 2019-10-01 Axovant Sciences Gmbh Geminal substituted aminobenzisoxazole compounds as agonists of α7-nicotinic acetylcholine receptors
JP2018526371A (ja) 2015-08-27 2018-09-13 ジェネンテック， インコーポレイテッド 治療化合物及びその使用方法
AU2016312848A1 (en) * 2015-08-27 2018-03-29 Auckland Uniservices Limited Inhibitors of tryptophan dioxygenases (IDO1 and TDO) and their use in therapy
RU2018115718A (ru) 2015-09-28 2019-10-28 Дженентек, Инк. Терапевтические соединения и способы их применения
EP3380466A1 (fr) 2015-11-25 2018-10-03 Genentech, Inc. Benzamides substitués utiles en tant que bloqueurs de canaux sodiques
EP3436432B1 (fr) 2016-03-30 2021-01-27 Genentech, Inc. Benzamides substitués et leurs méthodes d'utilisation
MX2019004232A (es) 2016-10-17 2019-08-01 Genentech Inc Compuestos terapéuticos y métodos para utilizarlos.
EP3601273B1 (fr) 2017-03-24 2021-12-01 Genentech, Inc. Dérivés de 4-pipéridine-n-(pyrimidin-4-yl) chromane-7-sulfonamide en tant qu'inhibiteurs de canaux sodiques
EP3759098A1 (fr) 2018-02-26 2021-01-06 Genentech, Inc. Composés de pyridine-sulfonamide et leur utilisation contre la douleur et les états associés
JP2021519788A (ja) 2018-03-30 2021-08-12 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ ナトリウムチャネル阻害剤としての縮合環ヒドロピリド化合物
GB201810581D0 (en) 2018-06-28 2018-08-15 Ctxt Pty Ltd Compounds
RS64931B1 (sr) 2019-06-18 2023-12-29 Pfizer Derivati benzizoxazol sulfonamida
BR112022010522A2 (pt) 2019-12-04 2022-08-16 Syngenta Crop Protection Ag Compostos amino heteroaromáticos, bicíclicos, fundidos e pesticidamente ativos
WO2021151926A1 (fr) 2020-01-30 2021-08-05 Syngenta Crop Protection Ag Composés aminés hétéroaromatiques bicycliques condensés à action pesticide
CN112142683B (zh) * 2020-09-01 2022-05-24 成都大学 一种氮杂十一元环化合物及其制备方法、用途以及包含该化合物的药物

Family Cites Families (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2119920C1 (ru) * 1991-03-28 1998-10-10 Эйсай Ко., Лтд. Гетероцикло-циклические производные аминов или их фармацевтически приемлемые соли, промежуточные соединения, фармацевтическая композиция, способ ингибирования холинэстеразы, способ получения соединений
US5328920A (en) * 1991-04-17 1994-07-12 Hoechst-Roussel Pharmaceuticals Incorporated Substituted (pyridinylamino)-indoles
DE69332691T2 (de) * 1992-11-23 2003-12-18 Aventis Pharma Inc Substituierte 3-(aminoalkylamino)-1,2-benzisoxazole und verwandte verbindungen
US5494908A (en) * 1992-11-23 1996-02-27 Hoechst-Roussel Pharmaceutical Incorporated Substituted 3-(aminoalkylamino)-1,2-benzisoxazoles and related compounds
MX9709451A (es) * 1995-06-06 1998-02-28 Hoechst Marion Roussel Inc Derivados de benzisoxazol e indazol como agentes antipsicoticos.
DE69918148T2 (de) * 1998-10-06 2005-07-28 Janssen Pharmaceutica N.V. Trizyclische delta3-pyridine als arzneimittel
AU1616600A (en) * 1998-11-12 2000-05-29 Eli Lilly And Company Aminobenzisoxazole compounds and libraries thereof
WO2000027627A1 (fr) * 1998-11-12 2000-05-18 Eli Lilly And Company Lieurs d'aryloxime dans la synthese de la phase solide de 3-aminobenzisoxazoles
ATE268766T1 (de) * 1999-07-16 2004-06-15 Bristol Myers Squibb Pharma Co Stickstoff enthaltende heterobicyclen als factor xa inhibitoren
US20030176454A1 (en) * 2000-05-15 2003-09-18 Akira Yamada N-coating heterocyclic compounds
US6469042B1 (en) * 2001-02-20 2002-10-22 Bristol-Myers Squibb Company Fluoro oxindole derivatives as modulators if KCNQ potassium channels
MXPA03007397A (es) 2001-02-20 2003-12-04 Bristol Myers Squibb Co Moduladores de canales de potasio kcnq y uso de los mismos en tratamiento de migrana y enfermedades mecanicamente relacionadas.
EP1361879A1 (fr) * 2001-02-20 2003-11-19 Bristol-Myers Squibb Company Derives de 2,4-disubstitue pyrimidine-5-carboxamide en tant que modulateur des canaux potassium kcnq
US6593349B2 (en) * 2001-03-19 2003-07-15 Icagen, Inc. Bisarylamines as potassium channel openers
KR100789567B1 (ko) * 2001-11-06 2007-12-28 동화약품공업주식회사 3-아미도-1,2-벤조이소옥사졸 유도체, 그 염, 제조방법 및 용도
DE10229070A1 (de) * 2002-06-28 2004-01-15 Merck Patent Gmbh Phenylderivate 5
GB0217757D0 (en) * 2002-07-31 2002-09-11 Glaxo Group Ltd Novel compounds
JO2696B1 (en) * 2002-12-23 2013-03-03 شركة جانسين فارماسوتيكا ان. في Derivatives of 1-piperdine-4-yl-4-biprolidine-3-yl-piperazine substituted and used as quinine antagonists
DK1638941T3 (da) * 2003-05-22 2010-10-11 Abbott Lab Indazol-, benzisoxazol- og benzisothiazolkinaseinhibitorer
GB0319150D0 (en) * 2003-08-14 2003-09-17 Glaxo Group Ltd Novel compounds
EP1746991A2 (fr) * 2004-03-16 2007-01-31 Janssen Pharmaceutica N.V. Benzisoxazoles inhibiteurs de daao pour le traitement des troubles de l'humeur
US7759337B2 (en) * 2005-03-03 2010-07-20 Amgen Inc. Phthalazine compounds and methods of use
DE102005038947A1 (de) * 2005-05-18 2006-11-30 Grünenthal GmbH Substituierte Benzo[d]isoxazol-3-yl-amin-Verbindungen und deren Verwendung in Arzneimitteln
DE102005026194A1 (de) * 2005-06-06 2006-12-07 Grünenthal GmbH Substituierte N-Benzo[d]isoxazol-3-yl-amin-Derivate und deren Verwendung zur Herstellung von Arzneimitteln
US7989461B2 (en) * 2005-12-23 2011-08-02 Amgen Inc. Substituted quinazolinamine compounds for the treatment of cancer

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2006122800A1 *

Also Published As

Publication number Publication date
CA2608773A1 (fr) 2006-11-23
DE502006004453D1 (de) 2009-09-17
EP1888541B1 (fr) 2009-08-05
PT1881967E (pt) 2010-06-30
US7696238B2 (en) 2010-04-13
ATE438633T1 (de) 2009-08-15
SI1881967T1 (sl) 2010-08-31
PL1888541T3 (pl) 2010-01-29
CY1110209T1 (el) 2015-01-14
ATE466002T1 (de) 2010-05-15
JP2008540597A (ja) 2008-11-20
RU2007146385A (ru) 2009-10-27
WO2006122799A1 (fr) 2006-11-23
RU2416607C2 (ru) 2011-04-20
DE102005038947A1 (de) 2006-11-30
CA2608386A1 (fr) 2006-11-23
ES2331259T3 (es) 2009-12-28
ES2344272T3 (es) 2010-08-23
AU2006249065A1 (en) 2006-11-23
US7977360B2 (en) 2011-07-12
HK1112238A1 (en) 2008-08-29
EP1881967B1 (fr) 2010-04-28
CY1109568T1 (el) 2014-08-13
PT1888541E (pt) 2009-11-10
JP2008540598A (ja) 2008-11-20
EP1888541A1 (fr) 2008-02-20
DE502006006854D1 (de) 2010-06-10
SI1888541T1 (sl) 2010-01-29
US20090042945A1 (en) 2009-02-12
PL1881967T3 (pl) 2010-10-29
AU2006249065B2 (en) 2011-04-21
DK1888541T3 (da) 2009-12-07
WO2006122800A1 (fr) 2006-11-23
DK1881967T3 (da) 2010-08-16
US20080176915A1 (en) 2008-07-24

Similar Documents

Publication Publication Date Title
EP1881967A1 (fr) Composes benzo(d)isoaxol-3-yl-amine substitues utilises comme analgesiques
EP1888596B1 (fr) Composes spiro substitues, et leur utilisation pour produire des medicaments contre la douleur
EP1910381B1 (fr) Composes de 1-oxa-3,8-diazaspiro[4.5]-decane-2-one substitues et utilisation de ceux-ci pour produire des medicaments
EP1497279B1 (fr) Indoles substitues et leur utilisation comme inhibiteurs de recapture 5ht et comme ligands 5ht
EP2146959B1 (fr) Ligands de récepteur vanilloïde et leur utilisation pour la fabrication de médicaments
EP2292625B1 (fr) Composes spiro substitues, et leur utilisation pour produire des medicaments contre la douleur
EP1730147A1 (fr) Composes 1,4,8-triazaspiro[4.5]decan-2-one substitues pour traiter l'obesite
EP1869038B1 (fr) Composes substitues de 5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine-2-ylamine et leur utilisation pour produire des medicaments
DE102007044277A1 (de) Substituierte Nicotinamid-Verbindungen und deren Verwendung in Arzneimitteln
DE102007018149A1 (de) Neue Vanilloid-Rezeptor Liganden und ihre Verwendung zur Herstellung von Arzneimitteln
EP1888542A1 (fr) Composes spiro substitues, et leur utilisation pour produire des medicaments
EP1890695B1 (fr) Utilisation de derives de thiazol-4-one 2,5-disubstitues dans des medicaments
EP1869053B1 (fr) Composes 4,5,6,7-tetrahydro-isoxazolo[4,5-c]pyridine substitues et leur utilisation pour produire des medicaments
DE102005018191A1 (de) Substituierte zyklische Harnstoff-Derivate und deren Verwendung zur Herstellung von Arzneimitteln
WO2005077924A1 (fr) Composes 4,5,6,7-tetrahydro-benzothiazol-2-ylamine substitues
EP1891035B1 (fr) Derives de cycloheptanone benzocondenses substitues, et leur utilisation pour produire des medicaments
DE102005039145A1 (de) Substituierte benzokondensierte Cyclohexanon-Derivate und deren Verwendung zur Herstellung von Arzneimitteln
DE102005050408A1 (de) Neue Vanilloidrezeptor-Liganden und ihre Verwendung zur Herstellung von Arzneimitteln

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20071030

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

DAX Request for extension of the european patent (deleted)
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1112238

Country of ref document: HK

17Q First examination report despatched

Effective date: 20090417

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

Free format text: NOT ENGLISH

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

Ref country code: CH

Ref legal event code: NV

Representative=s name: BRAUNPAT BRAUN EDER AG

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

Free format text: LANGUAGE OF EP DOCUMENT: GERMAN

REF Corresponds to:

Ref document number: 502006006854

Country of ref document: DE

Date of ref document: 20100610

Kind code of ref document: P

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: PT

Ref legal event code: SC4A

Free format text: AVAILABILITY OF NATIONAL TRANSLATION

Effective date: 20100623

REG Reference to a national code

Ref country code: NL

Ref legal event code: T3

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20100401528

Country of ref document: GR

REG Reference to a national code

Ref country code: RO

Ref legal event code: EPE

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

Ref country code: EE

Ref legal event code: FG4A

Ref document number: E004368

Country of ref document: EE

Effective date: 20100625

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2344272

Country of ref document: ES

Kind code of ref document: T3

REG Reference to a national code

Ref country code: HU

Ref legal event code: AG4A

Ref document number: E008055

Country of ref document: HU

REG Reference to a national code

Ref country code: SK

Ref legal event code: T3

Ref document number: E 7570

Country of ref document: SK

REG Reference to a national code

Ref country code: PL

Ref legal event code: T3

REG Reference to a national code

Ref country code: HK

Ref legal event code: GR

Ref document number: 1112238

Country of ref document: HK

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20110131

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20120607

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 20120426

Year of fee payment: 7

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BG

Payment date: 20130328

Year of fee payment: 8

Ref country code: MC

Payment date: 20130326

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: PL

Payment date: 20130314

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DK

Payment date: 20130513

Year of fee payment: 8

Ref country code: CY

Payment date: 20130411

Year of fee payment: 8

Ref country code: LT

Payment date: 20130417

Year of fee payment: 8

Ref country code: GB

Payment date: 20130515

Year of fee payment: 8

Ref country code: EE

Payment date: 20130416

Year of fee payment: 8

Ref country code: SE

Payment date: 20130513

Year of fee payment: 8

Ref country code: IE

Payment date: 20130510

Year of fee payment: 8

Ref country code: IS

Payment date: 20130404

Year of fee payment: 8

Ref country code: LU

Payment date: 20130529

Year of fee payment: 8

Ref country code: CH

Payment date: 20130514

Year of fee payment: 8

Ref country code: SK

Payment date: 20130503

Year of fee payment: 8

Ref country code: CZ

Payment date: 20130514

Year of fee payment: 8

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 20130531

Year of fee payment: 8

Ref country code: HU

Payment date: 20130423

Year of fee payment: 8

Ref country code: GR

Payment date: 20130412

Year of fee payment: 8

Ref country code: FI

Payment date: 20130513

Year of fee payment: 8

Ref country code: TR

Payment date: 20130425

Year of fee payment: 8

Ref country code: IT

Payment date: 20130520

Year of fee payment: 8

Ref country code: NL

Payment date: 20130510

Year of fee payment: 8

Ref country code: SI

Payment date: 20130422

Year of fee payment: 8

Ref country code: LV

Payment date: 20130422

Year of fee payment: 8

Ref country code: RO

Payment date: 20130411

Year of fee payment: 8

Ref country code: PT

Payment date: 20130517

Year of fee payment: 8

Ref country code: FR

Payment date: 20130531

Year of fee payment: 8

REG Reference to a national code

Ref country code: PT

Ref legal event code: MM4A

Free format text: LAPSE DUE TO NON-PAYMENT OF FEES

Effective date: 20141118

REG Reference to a national code

Ref country code: NL

Ref legal event code: V1

Effective date: 20141201

REG Reference to a national code

Ref country code: LT

Ref legal event code: MM4D

Effective date: 20140518

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140518

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: DK

Ref legal event code: EBP

Effective date: 20140531

REG Reference to a national code

Ref country code: EE

Ref legal event code: MM4A

Ref document number: E004368

Country of ref document: EE

Effective date: 20140531

Ref country code: AT

Ref legal event code: MM01

Ref document number: 466002

Country of ref document: AT

Kind code of ref document: T

Effective date: 20140518

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20140518

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140518

Ref country code: EE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140531

Ref country code: GR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20141203

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140531

Ref country code: PT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20141118

Ref country code: FI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140518

Ref country code: CZ

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140518

Ref country code: RO

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140518

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140531

Ref country code: BG

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20141231

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140519

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140602

Ref country code: SK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140518

REG Reference to a national code

Ref country code: GR

Ref legal event code: ML

Ref document number: 20100401528

Country of ref document: GR

Effective date: 20141203

REG Reference to a national code

Ref country code: SK

Ref legal event code: MM4A

Ref document number: E 7570

Country of ref document: SK

Effective date: 20140518

REG Reference to a national code

Ref country code: SE

Ref legal event code: EUG

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140519

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20141201

Ref country code: LV

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140518

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20141201

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140518

Ref country code: CY

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140518

Ref country code: HU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140519

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20150130

Ref country code: SI

Ref legal event code: KO00

Effective date: 20150106

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140531

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140518

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140518

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140602

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140518

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20150626

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140519

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140518

REG Reference to a national code

Ref country code: PL

Ref legal event code: LAPE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140531

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20140518

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20220531

Year of fee payment: 17

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 502006006854

Country of ref document: DE

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20231201